7-(Oxoalkyl)-1,3-dialkyl xanthines, and medicaments containing them

ABSTRACT

7-(Oxoalkyl)-1,3-dialkyl xanthines whose substituents in the 1- and 3-positions are alkyl groups of 2 to 6 carbons, cyclohexyl, alkoxyalkyl or hydroxyalkyl, such as 7-(3-oxobutyl)-1,3-di-n-butylxanthine, are effective vasodilators, having a marked activity in promoting blood flow through skeletal muscle, while at the same time exhibiting low toxicity.

This is a continuation of Ser. No. 753,931 filed Dec. 23, 1976 now abandoned which itself is a continuation of Ser. No. 542,449 filed Jan. 20, 1975, now abandoned.

The preparation of 7-(oxoalkyl)-1,3-dimethyl xanthines is described in DT-AS No. 1,233,405. These compounds are described as effective, substantially non-toxic vasodilators. In addition, the preparation of 1-(oxoalkyl)-3,7-dimethyl xanthines is known from DT-AS No. 1,235,320. These compounds are also significant vasodilators.

It has now been found that certain, hitherto unknown 7-(oxoalkyl)-1,3-dialkyl xanthines are very effective in increasing blood flow through skeletal muscle whilst at the same time showing low toxicity.

Accordingly, the present invention relates to 7-(oxoalkyl) 1,3-dialkyl xanthines corresponding to the general formula ##STR1## in which R₁ and R₂ are the same and/or different and represent straight-chain or branched alkyl radicals with 2 to 6 carbon atoms, cyclohexyl, alkoxyalkyl and hydroxyalkyl radicals, and A represents a hydrocarbon radical with up to 4 carbon atoms which may be constituted by a methyl group.

Suitable alkyl groups include ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, hexyl and the like. Alkoxy substituted alkyl groups are those containing from 2 to 6 carbons in the combined alkoxy and alkyl groups, including methoxymethyl, amyloxymethyl, methoxyethyl, butoxyethyl, propoxypropyl and the like. Hydroxyalkyl groups are those containing from 1 to 6 carbons, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyhexyl, and the like.

The hydrocarbon groups represented by A are divalent saturated aliphatic hydrocarbon groups, i.e., methylene, ethylene, trimethylene and tetramethylene, which may be substituted on the carbon adjacent the carbonyl group with methyl. Such methyl-substituted groups include ethylidine, 1,2-propylene, and 1,3-butylene.

The claimed compounds are prepared in known manner at elevated temperature, optionally in the presence of a solvent, either

(a) by reacting correspondingly substituted 1,3-dialkyl xanthines corresponding to the general formula ##STR2## in which R₁ and R₂ are as defined above, with α,β-unsaturated methyl ketones corresponding to the general formula ##STR3## in which R represents hydrogen or a methyl group, in alkaline medium at elevated temperature, or

(b) by reacting alkali metal salts of 1,3-dialkyl xanthine derivatives of general formula II, in which R₁ and R₂ are as defined above, with oxoalkyl halides corresponding to the general formula ##STR4## in which A is as defined above and Hal represents a halogen atom, preferably chlorine or bromine.

The described reactions are preferably carried out at temperatures in the range from 40° to 80° C., optionally under elevated or reduced pressure, but usually at atmospheric pressure. The individual starting compounds may be used either in stoichiometric quantities or in excess. The alkali salts in reaction (b) may either be prepared beforehand or in the reaction itself.

Suitable solvents are water-miscible compounds, preferably lower alcohols such as methanol, propanol, isopropanol, and various butanols, also acetone, pyridine, triethylamine, polyhydric alcohols such as ethylene glycol, and ethylene glycol monomethyl/(ethyl) ether.

The compounds prepared in accordance with the invention are distinguished by their marked effect in increasing blood flow through skeletal muscle and by their low toxicity. The most active of the compounds prepared in accordance with the invention is 7-(3-oxobutyl)-1,3-di-n-butyl xanthine.

Accordingly, the invention also relates to medicaments containing a compound of formula I as active principle.

The tests described hereinafter demonstrate this activity. They were carried out with male and female cats (under urethanechloralose anaesthesia). The compounds were applied intra duodenally in methyl cellulose suspension. Blood pressure, heart rate and blood flow were determined in the usual way using a Statham transducer and heat-conduction probes. The data obtained (cf. Table I) demonstrate the marked activity of the compounds according to the invention in promoting blood flow through skeletal muscle. In this respect, the compounds according to the invention are far superior to the comparison compounds used, for example pentoxy phylline (cf. Table II). The ratio between the increase in blood flow through skeletal muscle and the increase in heart rate is favorable. The results obtained are graphically recorded in FIGS. 1 and 2.

                  TABLE I                                                          ______________________________________                                         7-(3-Oxobutyl)-1,3-di-n-butylxanthine                                          ______________________________________                                                         in cats      Duration                                          Blood pressure(Bp)                                                                             change in %  in minutes                                        ______________________________________                                          5  mg/kg       +10.5        38.8                                              12.6 mg/kg      +9.7         57.3                                              31.5 mg/kg      +9.7         40.0                                              63.0 mg/kg      -7.7         25.0                                              ______________________________________                                                                      Duration                                          Heart rate (HR) change in %  in minutes                                        ______________________________________                                          7  mg/kg       +12.7        >49.0                                             12.6 mg/kg      +13.8        55.9                                              31.5 mg/kg      +7.1         61.0                                              63.0 mg/kg      -0.9         40.0                                              ______________________________________                                         Skeletal muscle                                                                heat-transfer                Duration                                          coefficient     change in %  in minutes                                        ______________________________________                                          5  mg/kg       +28.8        72.0                                              12.6 mg/kg      +29.3        77.0                                              31.5 mg/kg      +24.5        75.0                                              63.0 mg/kg      +12.0        26.0                                              ______________________________________                                          N = 6 in all dosages                                                     

                  TABLE II                                                         ______________________________________                                         Pentoxyphylline in cats                                                        ______________________________________                                                         in cats      Duration                                          Blood Pressure (Bp)                                                                            change in %  in minutes                                        ______________________________________                                          5 mg/kg        ± 0       --                                                10 mg/kg        + 3          10                                                30 mg/kg        + 3          19                                                50 mg/kg        - 3          >28                                               ______________________________________                                                                      Duration                                          Heart rate (HR) change in %  in minutes                                        ______________________________________                                          5 mg/kg        + 9          >27                                               10 mg/kg        + 10         >30                                               30 mg/kg        + 20         >21                                               50 mg/kg        + 10         >26                                               ______________________________________                                         Skeletal muscle                                                                heat-transfer                Duration                                          coefficient     change in %  in minutes                                        ______________________________________                                          5 mg/kg        + 10         20                                                10 mg/kg        + 4          12                                                30 mg/kg        + 2          17                                                50 mg/kg        ± 0       --                                                ______________________________________                                    

The influence on the pO₂, pCO₂ and pH of arterial and venous blood was investigated in bastard dogs (under urethane-chloralose anaesthesia). To this end, blood was taken from the A. aorta and from the V. femoralis at intervals of 5 minutes.

The test compounds, namely 7-(3-oxobutyl)-1,3-di-n-butyl xanthine and, for comparison, pentoxy phylline, were administered intravenously.

The results are graphically recorded in FIGS. 3 and 4.

The intravenous administration in a single dose of 30 mg of 7-(3-oxobutyl)-1,3-di-n-butyl xanthine per kg shows that this compound distinctly increases the pO₂ both in the arterial side and also in the venous side of the circuit for a period of 70 minutes at least. This increase in pO₂ is more persistent than the increase produced with pentoxy phylline.

The LD₅₀ of the compound in mice is more than 1000 mg/kg per os and 134 mg/kg i.v.

The vivo tests on the brains of rats showed an increased comsumption of oxygen after a single dose of 100 mg/kg of 7-(3-oxobutyl)-1,3-di-n-butyl xanthine p.o. by comparison with a control with methyl cellulose suspension (cf. Table III and FIG. 5).

Examination of parmeters from fat and carbohydrate metabolism shows that the compound does not have the usual properties of xanthine derivatives, such as increasing lipolysis and increasing the glucose and lactate level in the blood of normal rats, and intensifying the adrenalin effect. On the contrary, the above-mentioned parameters are in some cases significantly reduced and the changes brought about by adrenalin even further intensified by the administration of 7-(3-oxobutyl)-1,3-di-n-butyl xanthine (cf. Tables IV to VI).

The other compounds according to the invention show equally marked pharmacological activity.

                                      TABLE III                                    __________________________________________________________________________     μl O.sub.2 - consumption of fresh weight                                    of rat's brain in vivo (in methyl cellulose suspension)                        + 100 mg/kg of 7-(3-oxobutyl)-1,3-di-n-butylxanthine p.o. 2 hrs. before        killing                                                                        Animal                                                                             Weight                                                                     No. ♀                                                                       g   10 mins.                                                                            20 mins.                                                                            30 mins.                                                                            40 mins.                                                                            50 mins.                                                                            60 mins.                                      __________________________________________________________________________     1   172 -250.7                                                                              -458.3                                                                              -654.3                                                                              -831.8                                                                              -970.1                                                                              -1132.0                                       2   186 -207.5                                                                              -407.6                                                                              -596.5                                                                              -763.8                                                                              -920.1                                                                              -1105.3                                       3   177 -275.0                                                                              -520.3                                                                              -728.4                                                                              -921.7                                                                              -1100.1                                                                             -1189.3                                       4   176 -183.0                                                                              -426.8                                                                              -602.0                                                                              -754.5                                                                              -914.5                                                                              -1059.3                                       5   187 -197.9                                                                              -395.6                                                                              -586.4                                                                              -752.9                                                                              -915.6                                                                              -1064.4                                       6   176 -197.1                                                                              -370.3                                                                              -546.9                                                                              -699.8                                                                              -862.9                                                                              -995.3                                        7   205 -220.1                                                                              -429.7                                                                              -606.8                                                                              -763.1                                                                              -940.9                                                                              -1083.6                                       8   200 -209.7                                                                              -349.6                                                                              -535.0                                                                              -698.7                                                                              -850.7                                                                              -1014.9                                       9   198 -233.3                                                                              -438.2                                                                              -646.7                                                                              -805.7                                                                              -978.8                                                                              -1109.6                                       10  196 -224.6                                                                              -436.9                                                                              -649.2                                                                              -861.6                                                                              -1012.6                                                                             -1269.9                                       0/  187 -219.9                                                                              -423.3                                                                              -614.3                                                                              -785.4                                                                              -946.6                                                                              -1102.4                                       %         3.6                                                                                 4.3                                                                                 3.8                                                                                 4.2                                                                                 4.4                                                                                 10.2                                        signifi-                                                                       cance   --   --   --   --   --   p < 0.01                                      __________________________________________________________________________     Control                                                                        (methyl cellulose suspension p.o.)                                             Animal                                                                             Weight                                                                     No. ♀                                                                       g   10 mins.                                                                            20 mins.                                                                            30 mins.                                                                            40 mins.                                                                            50 mins.                                                                            60 mins.                                      __________________________________________________________________________     1   184 -217.7                                                                              -428.7                                                                              -598.6                                                                              -757.8                                                                              -945.8                                                                              -1024.8                                       2   162 -220.5                                                                              -404.6                                                                              -580.0                                                                              -750.7                                                                              -918.4                                                                              -1004.9                                       3   175 -235.7                                                                              -484.6                                                                              -683.8                                                                              -908.2                                                                              -1026.9                                                                             -1106.8                                       4   165 -213.5                                                                              -388.2                                                                              -575.8                                                                              -737.5                                                                              -899.2                                                                              -989.8                                        5   166 -194.3                                                                              -388.7                                                                              -556.2                                                                              -690.2                                                                              -817.5                                                                              -931.5                                        6   185 -192.5                                                                              -358.4                                                                              -544.2                                                                              -703.5                                                                              -829.6                                                                              -929.2                                        7   202 -207.2                                                                              -393.7                                                                              -594.0                                                                              -759.7                                                                              -918.6                                                                              -1015.3                                       8   181 -184.4                                                                              -371.9                                                                              -520.6                                                                              -698.4                                                                              -834.3                                                                              -973.4                                        9   179 -245.0                                                                              -424.9                                                                              -638.7                                                                              -787.5                                                                              -942.7                                                                              -1030.4                                       10  192 -211.1                                                                              -415.3                                                                              -626.3                                                                              -746.9                                                                              -930.9                                                                              -997.7                                        φ                                                                              179 -212.2                                                                              -405.9                                                                              -591.8                                                                              -754.0                                                                              -906.4                                                                              -1000.4                                       __________________________________________________________________________

                  TABLE IV                                                         ______________________________________                                         7-(3-Oxobutyl)-1,3-di-n-butylxanthine - glucose level                          Rats:     starve for 5 hours, anaesthetise with ether,                                   cardiac puncture                                                     Method:   Bochringer test kit                                                            Animal                                                                               Weight                                                                   No. ♀                                                                         g       E.sub.1                                                                               E.sub.2                                                                             E.sub.2 -E.sub.1                                                                    mg %                                  ______________________________________                                         I. Normal   1       181     0.055                                                                               0.186                                                                               0.131                                                                               113.18                              (Methyl cellulose-                                                                         2       176     0.062                                                                               0.200                                                                               0.138                                                                               119.23                              suspension p.o.)                                                                           3       183     0.061                                                                               0.213                                                                               0.152                                                                               131.33                              2.sup.h before killing                                                                     4       168     0.064                                                                               0.182                                                                               0.118                                                                               101.95                              φ 117.07                                                                               5       172     0.057                                                                               0.207                                                                               0.150                                                                               129.60                                          6       170     0.062                                                                               0.186                                                                               0.124                                                                               107.14                              II. 7-(3-Oxobutyl)-                                                                        1       178     0.057                                                                               0.189                                                                               0.132                                                                               114.05                              1,3-di-n-butyl-                                                                            2       188     0.059                                                                               0.184                                                                               0.125                                                                               108.00                              xanthine    3       193     0.062                                                                               0.187                                                                               0.125                                                                               108.00                              100 mg/kg p.o.                                                                             4       189     0.062                                                                               0.182                                                                               0.120                                                                               103.68                              2.sup.h before killing                                                                     5       163     0.058                                                                               0.183                                                                               0.125                                                                               108.00                              φ 108.72                                                                               6       198     0.064                                                                               0.192                                                                               0.128                                                                               110.59                              III. Adrenalin                                                                             1       177     0.049                                                                               0.328                                                                               0.279                                                                               241.06                              1 mg/kg i.p.                                                                               2       170     0.062                                                                               0.292                                                                               0.230                                                                               198.72                              30' before killing                                                                         3       174     0.058                                                                               0.370                                                                               0.312                                                                               269.57                                          4       189     0.057                                                                               0.203                                                                               0.146                                                                               126.14                                          5       159     0.065                                                                               0.339                                                                               0.274                                                                               236.74                                          6       173     0.074                                                                               0.242                                                                               0.168                                                                               145.15                                          7       152     0.073                                                                               0.319                                                                               0.246                                                                               212.54                                          8       163     0.077                                                                               0.274                                                                               0.197                                                                               170.21                                          9       168     0.078                                                                               0.364                                                                               0.286                                                                               247.10                                          10      168     0.074                                                                               0.296                                                                               0.222                                                                               191.81                                          11      160     0.073                                                                               0.271                                                                               0.198                                                                               171.07                              φ 199.36                                                                               12      163     0.075                                                                               0.286                                                                               0.211                                                                               182.30                              IV. 7-(3-Oxobutyl)-                                                                        1       191     0.056                                                                               0.285                                                                               0.229                                                                               197.86                              1.3-di-n-butyl                                                                             2       165     0.053                                                                               0.180                                                                               0.127                                                                               109.73                              xanthine    3       185     0.055                                                                               0.251                                                                               0.196                                                                               169.34                              100 mg/kg BW                                                                               4       176     0.063                                                                               0.268                                                                               0.205                                                                               177.12                              oral        5       199     0.070                                                                               0.199                                                                               0.129                                                                               111.46                              2.sup.h before killing                                                                     6       181     0.069                                                                               0.330                                                                               0.261                                                                               225.50                                  +       7       152     0.068                                                                               0.193                                                                               0.125                                                                               108.00                              Adrenalin   8       163     0.073                                                                               0.193                                                                               0.120                                                                               103.68                              1 mg/kg i.p.                                                                               9       161     0.064                                                                               0.261                                                                               0.197                                                                               170.21                              30' before killing                                                                         10      169     0.069                                                                               0.262                                                                               0.193                                                                               166.75                              p > 0.05    11      162     0.073                                                                               0.296                                                                               0.223                                                                               192.67                              φ 159.12                                                                               12      178     0.083                                                                               0.288                                                                               0.205                                                                               177.12                              ______________________________________                                    

                                      TABLE V                                      __________________________________________________________________________     7-(3-Oxobutyl)-1,3-di-n-butylxanthine - Lactate level                          Rats:   starve for 5 hours, anaesthetise with ether, cardiac puncture          Method: Bochringer test kit                                                                  Animal                                                                             Weight                                                                     No. g   E.sub.P                                                                           E.sub.L                                                                           E.sub.P - E.sub.L                                                                   mg %                                          __________________________________________________________________________     I.                                                                               Normal      1   181 0.312                                                                             0.079                                                                             0.233                                                                               21.9                                            (Methyl cellulose-                                                                         2   176 0.277                                                                             0.079                                                                             0.198                                                                               18.6                                            suspension)                                                                    4 ml/kg BW p.o.                                                                            3   183 0.345                                                                             0.079                                                                             0.266                                                                               25.0                                            2.sup.h before killing                                                                     4   168 0.302                                                                             0.105                                                                             0.197                                                                               18.5                                                        5   172 0.325                                                                             0.105                                                                             0.220                                                                               20.7                                                        6   170 0.358                                                                             0.105                                                                             0.253                                                                               23.8                                                        7   160 0.328                                                                             0.095                                                                             0.233                                                                               21.9                                                        8   164 0.275                                                                             0.095                                                                             0.180                                                                               16.9                                                        9   170 0.333                                                                             0.095                                                                             0.238                                                                               22.4                                                        10  160 0.415                                                                             0.095                                                                             0.320                                                                               30.1                                                        11  167 0.405                                                                             0.095                                                                             0.310                                                                               29.2                                                                           φ 22.6                                    II.                                                                              7-(3-Oxobutyl)-                                                                            1   178 0.321                                                                             0.079                                                                             0.242                                                                               22.8                                            1,3-di-n-butyl-                                                                            2   188 0.230                                                                             0.079                                                                             0.151                                                                               14.2                                            xanthine    3   193 0.286                                                                             0.079                                                                             0.207                                                                               19.5                                            100 mg/kg BW p.o.                                                                          4   189 0.274                                                                             0.105                                                                             0.169                                                                               15.9                                            2.sup.h before killing                                                                     5   163 0.234                                                                             0.105                                                                             0.129                                                                               12.1                                                        6   198 0.224                                                                             0.105                                                                             0.119                                                                               11.2                                                        7   152 0.242                                                                             0.095                                                                             0.157                                                                               14.8                                                        8   157 0.252                                                                             0.095                                                                             0.157                                                                               14.8                                                        9   153 0.355                                                                             0.095                                                                             0.260                                                                               24.5                                                        10  149 0.274                                                                             0.095                                                                             0.179                                                                               16.8                                                        11  172 0.235                                                                             0.095                                                                             0.140                                                                               13.2                                            p < 0.01                       φ 16.2                                    II.                                                                              Adrenalin   1   189 0.730                                                                             0.079                                                                             0.651                                                                               61.3                                            1 mg/kg BW i.p.                                                                            2   194 0.345                                                                             0.105                                                                             0.240                                                                               22.6                                            30' before killing                                                                         3   159 0.768                                                                             0.105                                                                             0.663                                                                               62.4                                                        4   173 0.631                                                                             0.105                                                                             0.526                                                                               49.5                                                        5   148 0.763                                                                             0.105                                                                             0.658                                                                               61.9                                                        6   156 0.495                                                                             0.105                                                                             0.390                                                                               36.7                                                                           φ 49.0                                    V.                                                                               7-(3-Oxobutyl)-1,3-di-                                                                     1   191 0.638                                                                             0.079                                                                             0.559                                                                               52.6                                            n-butylxanthine                                                                            2   165 0.506                                                                             0.079                                                                             0.427                                                                               40.2                                            100 mg/kg BW p.o.                                                                          3   185 0.622                                                                             0.079                                                                             0.543                                                                               51.1                                            2.sup.h before killing                                                                     4   176 0.850                                                                             0.105                                                                             0.745                                                                               70.1                                            Adrenalin                                                                      1 mg/kg BW i.p.                                                                            5   199 0.552                                                                             0.105                                                                             0.447                                                                               42.1                                            30' before killing                                                                         6   181 0.705                                                                             0.105                                                                             0.600                                                                               56.5                                                                           φ 52.1                                    __________________________________________________________________________

                  TABLE VI                                                         ______________________________________                                         Serum fatty acids FFS                                                          Rats ♂, starve for 17 h., anaesthetise with ether,                        cardiac puncture                                                               7-(3-Oxobutyl-1,3-di-n-butylxanthine 160 mg/kg                                 Method: Acta Biol. Vol. 12, p. 520 (1964)                                                   Animal Weight                                                                  No.    g          μ val/ml                                     ______________________________________                                                        1        151        1.12                                        Control series 2        155        0.99                                        (methyl cellulose-                                                                            3        160        0.87                                        suspension)    4        175        0.87                                        4 mg/kg BW p.o.                                                                               5        168        0.81                                        2.sup.h before killing                                                                        6        160        0.73                                                       7        213        0.72                                                       8        200        0.76                                                       9        160        1.10                                                       10       150        0.99                                                                φ 169  0.90                                                       1        151        0.68                                        7-(3-Oxobutyl)-1,3-di-n-                                                                      2        152        0.76                                        butylxanthine  3        152        0.75                                        160 mg/kg BW p.o.                                                                             4        188        0.57                                        2.sup.h before killing                                                                        5        165        0.81                                                       6        170        0.96                                                       7        190        1.07                                                       8        190        1.02                                                       9        190        0.95                                                       10       184        0.90                                                       11       203        1.02                                                       12       152        1.14                                                                φ 174  0.89                                                       1        161        1.23                                                       2        152        1.36                                        Adrenalin      3        177        1.09                                        1 mg/kg BW i.p.                                                                               4        173        1.17                                        30' before killing                                                                            5        172        1.17                                                       6        167        1.10                                                       7        139        1.52                                                       8        133        1.60                                                       9        149        1.73                                                       10       147        1.49                                                       11       140        1.45                                                       12       142        1.31                                                                φ 154  1.35                                        7-(3-Oxobutyl)-1,3-di-n-                                                                      1        160        0.84                                        butylxanthine  2        152        0.99                                        160 mg/kg BW p.o.                                                                             3        150        0.96                                        2.sup.h before killing                                                                        4        168        1.28                                        +              5        160        1.86                                        Adrenalin      6        181        1.39                                        1 mg/kg BW i.p.                                                                               7        166        1.72                                        30' before killing                                                                            8        146        1.46                                                       9        142        1.67                                                       10       143        1.65                                                                φ 157  1.33                                        ______________________________________                                    

The invention is illustrated by the following Examples.

EXAMPLE 1 7-(3-oxobutyl)-1,3-di-n-butyl xanthine

264.8 g (1 mol) of 1,3-di-n-butyl xanthine, 84 g (1.2 mol) of methyl vinyl ketone, 1060 ml of methanol and 39.7 ml of triethylamine are introduced into a 3 liter capacity three-necked flask, and the mixture slowly heated with stirring to 40° to 45° C. The reaction solution is then kept at that temperature until hardly any 1,3-di-n-butyl xanthine can be detected by thin-layer chromatography. Reaction time, approximately 2 to 2.5 hours.

On completion of the reaction, water is added to this solution in small portions in such a quantity that an approximately 75 to 80% aqueous methanolic solution is formed. This solution is left standing for several hours in a refrigerator and the crystals formed are filtered off under suction. Another recrystallization from methanol-water gives 276 g (=80% of the theoretical) of 7-(3-oxobutyl)-1,3-di-n-butyl xanthine melting at 86° to 87° C.

Another 24 g of 7-(3-oxobutyl)-1,3-di-n-butyl xanthine are obtained by concentrating the methanolic mother liquors.

Total yield: 300 g=87% of the theoretical

    ______________________________________                                         Analysis:  C        H        N      O                                          ______________________________________                                         Calculated:                                                                               61.06    7.84     16.75  14.35%                                     Found:     60.92    7.81     16.96  14.34%                                     ______________________________________                                    

The compounds listed in Table VII below are similarly obtained by modification (a) of the claimed process.

                                      TABLE VII                                    __________________________________________________________________________                          (Starting    Melting point                                                                           Yield %                                                                              Combustion analysis:          Example              material)    °C.:recrystall-                                                                  of theor-                                                                            C    H  N  O                  No.  R.sub.1 R.sub.2 R    A       isation solvent                                                                         ethical                                                                              (calc:+)                      __________________________________________________________________________                                                      (found:++)                    1    n-C.sub.4 H.sub.9                                                                      n-C.sub.4 H.sub.9                                                                      H    CH.sub.2CH.sub.2                                                                       86-87           + 61.06                                                                            7.84                                                                              16.75                                                                             14.35                                                methanol/water                                                                          87    ++ 60.92                                                                            7.81                                                                              16.96                                                                             14.34              2    n-C.sub.4 H.sub.9                                                                      n-C.sub.4 H.sub.9                                                                      CH.sub.3                                                                             ##STR5##                                                                              46 petrol/ethanol                                                                        79    +62.05 ++62.20                                                                     8.10 8.13                                                                         16.08 16.02                                                                       13.78 13.52        3    CH(CH.sub.3).sub.2                                                                     CH(CH.sub.3).sub.2                                                                     CH.sub.3                                                                             ##STR6##                                                                              91 petrol                                                                                77    + 59.98 ++60.15                                                                    7.55 7.39                                                                         17.49 17.24                                                                       14.98 15.40        4    CH(CH.sub.3).sub.2                                                                     CH(CH.sub.3).sub.2                                                                     H    CH.sub.2CH.sub.2                                                                       73              + 58.81                                                                            7.24                                                                              18.29                                                                             15.67                                                ethanol  80    ++ 59.13                                                                            7.28                                                                              18.09                                                                             15.52              __________________________________________________________________________

EXAMPLE 5 7-(5'-oxohexyl)-1,3-dibutyl xanthine

21.5 g (0.12 mol) of freshly distilled 1-bromo-5-hexanone are dissolved in 200 ml of absolute ethanol in a 500 ml capacity flask, followed by the gradual dropwise addition at boiling temperature of 34.7 g (0.12 mol) of sodium 1,3-dibutyl xanthine dissolved in 200 ml of absolute ethanol. The solution is heated under reflux. The reaction is over after about 24 hours. Removal of the alcohol by distillation in a rotary evaporator leaves a solid white residue. This residue is introduced into an extraction tube in which it is extracted with petrol 40/80 in a Soxhlet apparatus until no more starting material can be detected. The petrol is distilled off in a rotary evaporator, leaving 25 g (0.069 mol) of 7-(5'-oxohexyl)-1,3-dibutyl xanthine, corresponding to 75% of the theoretical, based on the sodium 1,3-dibutyl xanthine reacted.

The crude product has a melting point of 80° to 82° C.

Pure 7-(5'-oxohexyl)-1,3-dibutyl xanthine melting at 88° C. is obtained by repeated recrystallization from isopropanol. C₁₉ H₃₀ N₄ O₃ (362.74)

    ______________________________________                                                  C      H        N        O                                            ______________________________________                                         Calculated:                                                                               62.96    8.34     15.48  13.24%                                     Found:     62.99    8.14     15.34  13.40%                                     ______________________________________                                    

The extraction residue is dissolved in ethanol and the resulting solution separated off from the sodium bromide. The solution is then concentrated to dryness and the residue recrystallized from ethanol. 75. g (0.0284 mol) of 1.3-dibutyl xanthine are recovered.

The compounds listed in Table VIII are similarly prepared by modification (b) of the claimed process.

                                      TABLE VIII                                   __________________________________________________________________________                                   Melting point                                                                          Yield %                                                                             Combustion analysis:                Example                       C.:recrystall-                                                                         of theor-                                                                           C    H  N  O                        No.  R.sub.1 R.sub.2 A        isation solvent                                                                        ethical                                                                             (calc:+) (found:++)                 __________________________________________________________________________     5    n-C.sub.4 H.sub.9                                                                      n-C.sub.4 H.sub.9                                                                      (CH.sub.2).sub.3CH.sub.2                                                                88            +62.96                                                                             8.34                                                                              15.48                                                                             13.24                                                  isopropanol                                                                            75   ++62.99                                                                             8.14                                                                              15.34                                                                             13.40                    6    CH(CH.sub.3).sub.2                                                                     CH(CH.sub.3).sub.2                                                                     (CH.sub.2).sub.3CH.sub.2                                                                103           +61.06                                                                             7.84                                                                              16.75                                                                             14.33                                                  petrol/ethanol                                                                         71   ++61.06                                                                             7.99                                                                              16.94                                                                             14.33                    7    n-C.sub.4 H.sub.9                                                                      n-C.sub.4 H.sub.9                                                                      CH.sub.2 106           +59.98                                                                             7.55                                                                              17.49                                                                             14.98                                                  petrol/ethanol                                                                         68   ++60.00                                                                             7.53                                                                              17.01                                                                             15.51                    8    CH(CH.sub.3).sub.2                                                                     CH(CH.sub.3).sub.2                                                                     CH.sub.2 149           +57.52                                                                             6.90                                                                              19.16                                                                             16.42                                                  petrol/ethanol                                                                         64   ++57.81                                                                             6.75                                                                              18.97                                                                             16.54                    9    n-C.sub.4 H.sub.9                                                                      n-C.sub.4 H.sub.9                                                                      (CH.sub.2).sub.2CH.sub.2                                                                73            +62.05                                                                             8.10                                                                              16.08                                                                             13.78                                                  petrol/ethanol                                                                         30   ++61.98                                                                             7.86                                                                              16.21                                                                             14.16                    10   CH(CH.sub.3).sub.2                                                                     CH(CH.sub.3).sub.2                                                                     (CH.sub.2).sub.2CH.sub.2                                                                72            +59.98                                                                             7.55                                                                              17.49                                                                             14.98                                                  petrol/ethanol                                                                         35   ++60.16                                                                             7.40                                                                              17.44                                                                             14.88                    11   n-C.sub.4 H.sub.9                                                                      n-C.sub.4 H.sub.9                                                                       ##STR7##                                                                               96 petrol/ethanol                                                                       90   +61.06 ++61.17                                                                     7.84 7.85                                                                         16.75 16.98                                                                       14.35 14.10              12   CH(CH.sub.3).sub.2                                                                     CH(CH.sub.3).sub.2                                                                      ##STR8##                                                                               92 petrol/ethanol                                                                       53   +58.81 ++58.90                                                                     7.24 7.17                                                                         18.29 18.27                                                                       15.67 15.92              __________________________________________________________________________ 

We claim:
 1. 7-(3-Oxobutyl)-1,3-di-n-butyl xanthine.
 2. The compound of claim 1 in solid form.
 3. The compound of claim 1 in essentially pure form.
 4. 7-(1-Methyl-3-oxobutyl)-1,3-di-n-butyl xanthine.
 5. The compound of claim 4 in solid form.
 6. The compound of claim 4 in essentially pure form.
 7. 7-(5-Oxohexyl)-1,3-di-n-butyl xanthine.
 8. The compound of claim 7 in solid form.
 9. The compound of claim 7 in essentially pure form.
 10. 7-(4-Oxopentyl)-1,3-di-n-butyl xanthine.
 11. The compound of claim 10 in solid form.
 12. The compound of claim 10 in essentially pure form.
 13. 7-(2-oxopropyl)-1,3-di-n-butyl xanthine in solid form.
 14. 7-(2-oxopropyl)-1,3-di-n-butyl xanthine in essentially pure form.
 15. 7-(1-Methyl-2-oxopropyl)-1,3-di-n-butyl xanthine.
 16. The compound of claim 15 in solid form.
 17. The compound of claim 15 in essentially pure form.
 18. A pharmaceutical composition useful for promoting the flow of blood through skeletal muscles in humans and animals which comprises a therapeutically effective amount of 7-(3-oxobutyl)-1,3-di-n-butyl xanthine in combination with a pharmaceutically acceptable carrier.
 19. A pharmaceutical composition useful for promoting the flow of blood through skeletal muscles in humans and animals which comprises a therapeutically effective amount of 7-(1-methyl-3-oxobutyl)-1,3-di-n-butyl xanthine in combination with a pharmaceutically acceptable carrier.
 20. A pharmaceutical composition useful for promoting the flow of blood through skeletal muscles in humans and animals which comprises a therapeutically effective amount of 7-(5-oxohexyl)-1,3-di-n-butyl xanthine in combination with a pharmaceutically acceptable carrier.
 21. A pharmaceutical composition useful for promoting the flow of blood through skeletal muscles in humans and animals which comprises a therapeutically effective amount of 7-(4-oxopentyl)-1,3-di-n-butyl xanthine in combination with a pharmaceutically acceptable carrier.
 22. A pharmaceutical composition useful for promoting the flow of blood through skeletal muscles in humans and animals which comprises a therapeutically effective amount of 7-(2-oxopropyl)-1,3-di-n-butyl xanthine in combination with a pharmaceutically acceptable carrier.
 23. A pharmaceutical composition useful for promoting the flow of blood through skeletal muscles in humans and animals which comprises a therapeutically effective amount of 7-(1-methyl-2-oxopropyl)-1,3-di-n-butyl xanthine in combination with a pharmaceutically acceptable carrier.
 24. A method of promoting the flow of blood through skeletal muscles in humans and animals which comprises administering to a human or animal in need thereof a therapeutically effective amount of 7-(3-oxobutyl)-1,3-di-n-butyl xanthine.
 25. A method of promoting the flow of blood through skeletal muscles in humans and animals which comprises administering to a human or animal in need thereof a therapeutically effective amount of 7-(1-methyl-3-oxobutyl)-1,3-di-n-butyl xanthine.
 26. A method of promoting the flow of blood through skeletal muscles in humans and animals which comprises administering to a human or animal in need thereof a therapeutically effective amount of 7-(5-oxohexyl)-1,3-di-n-butyl xanthine.
 27. A method of promoting the flow of blood through skeletal muscles in humans and animals which comprises administering to a human or animal in need thereof a therapeutically effective amount of 7-(4-oxopentyl)-1,3-di-n-butyl xanthine.
 28. A method of promoting the flow of blood through skeletal muscles in humans and animals which comprises administering to a human or animal in need thereof a therapeutically effective amount of 7-(2-oxopropyl)-1,3-di-n-butyl xanthine.
 29. A method of promoting the flow of blood through skeletal muscles in humans and animals which comprises administering in a human or animal in need thereof a therapeutically effective amount of 7-(1-methyl-2-oxopropyl)-1,3-di-n-butyl xanthine. 